Abstract 1142: Discovery of FMC-376 a novel orally bioavailable inhibitor of activated KRASG12C

KRAS is one of the most frequently mutated genes in cancer and was long considered undruggable until the recent discovery of inhibitors that bind the inactive (GDP-bound) form of KRASG12C. The most clinically advanced of these first-generation molecules have demonstrated clinical response rates of 30-45% and approximately 6-month progression-free survival in lung cancer patients. While significant, a majority of patients fail to achieve a clinical response and acquired resistance is common. Resistance to first-generation inhibitors can be driven by upregulation of the activated (GTP-bound) form of KRASG12C, which remains an undrugged form of the oncoprotein. Here we report the discovery of FMC-376, a novel inhibitor of the activated, GTP-bound, form of KRASG12C, which also potently inhibits the inactive, (GDP-bound), form of KRASG12C. FMC-376 was discovered through the FrontierTM platform, which integrates chemoproteomics, machine-learning, and covalent fragment-based drug discovery. FMC-376 binds KRAS in the switch II pocket, rapidly forming a covalent bond with cysteine 12 in the presence of either GDP or GTP. X-ray crystallography demonstrated that Cys12 adopts a novel confirmation in forming a covalent bond with FMC-376. This results in potent inhibition of RAF1 and PI3Kα effector interactions (IC50 = 0.007 μM for both respectively at 2 h) in contrast to sotorasib or adagrasib (IC50 > 50 and ~ 5 μM respectively). FMC-376 treatment results in potent anti-tumor activity across a panel of KRASG12C mutant tumor cell lines, sparing non- KRASG12C cell lines. To model resistance mediated by activated KRASG12C, a mutation that abrogates GTPase activity (A59G) was introduced into KRASG12C. This upregulation of GTP-bound KRASG12C drives significant (>10-fold) resistance to both adagrasib and sotorasib in tumor cell viability assays whereas FMC-376 remains equipotent in settings where GTP-bound KRASG12C is upregulated. Evaluation of FMC-376 in models where EGFR signaling (a suspected mechanism of clinical resistance) is induced demonstrated rapid and durable target engagement in contrast to both sotorasib and adagrasib which show decreased effectiveness after EGF stimulation. Further evaluation of FMC-376 in vivo has demonstrated rapid and durable KRASG12C target occupancy (>90%) and pathway inhibition in tumors, resulting in regression of CDX/PDX tumor models. FMC-376, an inhibitor of both active and inactive forms of KRASG12C, provides a differentiated mechanism of action with the potential for broader and more durable response in the clinic. Citation Format: Snahel Patel, Barun Bhhatarai, Philamer Calses, Daniel Erlanson, Robert Everley, Susan Fong, Phil Gerken, Johannes C. Hermann, Tiep Le, Li-kai Liu, Evan McMahon, Richard M. Neve, Tony Phan, Allison Roberts, Mikayla Shanafelt, Sophie Siemsgluess, Jocelyn Staunton, Yan Wang, Weiru Wang, Monika Williams, Kevin R. Webster. Discovery of FMC-376 a novel orally bioavailable inhibitor of activated KRASG12C [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1142.